The goal of these studies is to define the role of growth factors (GFs) in the regulation of differentiation of normal and malignant B cells, on both a cellular and molecular level. B cell mitogens (M) and recombinant GFs, interleukin 4 (IL-4) and IL-6, will be used to develop new in vitro systems for differentiation of B cells. In vivo B cell differentiation will be delineated by utilizing enrichment techniques and dual laser cell sorting to purify B cells from splenocytes and hyperplastic lymph nodes in normal and autoimmune disease states, and then similarly characterizing their response to M/GFs. In both in vitro and in vivo systems, the mechanisms of GF response will be determined by examining associated intracellular characteristics (GF production evidenced by GF mRNA and intracellular GF; cytoplasmic u or Ig); cell membrane events (calcium flux, cell surface expression for B cell antigens and GF receptors); and functional repertoire (cell cycle profile, DNA synthesis, and immunoglobulin secretion). In parallel studies, the role of GFs in regulation of malignant B cells will be studied. B cell tumors will be examined for receptors for and mechanisms of response to IL- 3, IL-4 and IL-6. The mechanisms of response of purified myeloma cells and derived cell lines to M/GFs in liquid and semisolid cultures will be defined at a cellular and molecular level. In order to identify the morphologic, phenotypic, functional and biological characteristics of those cells within the myeloma clone which may be self-renewing. Somatic cell hybridization using these cells as the immunogen will be used to generate new monoclonal antibodies (MoAbs) against cell surface antigens on these cells. These studies may not only define the biology of the myeloma stem cell but also suggest new strategies to alter its growth and/or differentiation in vivo. Alternatively, they may provide a method for the specific and complete removal of myeloma stem cells from autologous bone marrow to facilitate the development of new treatment strategies for these presently incurable diseases. Preliminary studies have demonstrated that complete responses in myeloma can be achieved using high doses of chemoradiotherapy followed by reinfusion of autologous bone marrow that has been treated in vitro with MoAbs and complement to deplete tumor cells. Although these studies are encouraging, relapses suggest that improvements in ablative therapies in vivo and/or marrow purging methods in vitro are needed.